PROJECT 3: Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) contributes to 6.9% of all cancer deaths in the US, and >1.5% of the US population will be diagnosed with PDAC in their lifetime. At present, the front-line therapy for advanced PDAC is multi-agent chemotherapy, most commonly, FOLFIRINOX or gemcitabine and nab-paclitaxel. Despite a better understanding of the genomic landscape and the importance of the tumor?s microenvironment, there has been no meaningful shift in the overall survival for this disease. An emerging concept is that mutations in KRAS and other canonical oncogenes that drive accelerated growth in PDAC and other tumors also directly reprogram cellular metabolism by augmenting nutrient acquisition, coupled to an increased flux through downstream metabolic pathways. Differential dependence on KRAS has also been linked with altered metabolic dependencies. The findings above indicate that the heterogeneity of PDAC is not only defined on the genomic and cellular levels, but also defined by distinctive metabolism programs controlled by oncogenic signaling. However, to date, the documented dependency of some tumors or tumor cell subpopulations on OXPHOS has not yet been exploited therapeutically. The University of Texas MD Anderson Cancer Center Institute for Applied Cancer Science (IACS) has developed IACS-010759, a potent inhibitor of complex I of the electron transport chain. The IACS compound has enabled expanded studies of OXPHOS inhibition in PDAC models that establish the preclinical rationale for evaluating IACS-010759 in patients in two contexts: (i) patients with treatment-nave or refractory tumors that possess intrinsic sensitivity to OXPHOS inhibition, and (ii) in metabolically adapted disease following treatment with chemotherapy. The aims of this study are to explore the biology of response to treatment with IACS-010759 in these contexts, using a combination of ex vivo and in vivo studies, as well as evaluating patient response via clinical correlatives (transcriptomic signatures, hyperpolarized pyruvate-magnetic resonance imaging, quantitative CT scan) in planned phase 1b and phase 2a clinical studies in patients with treatment-nave or refractory disease (phase 1b) or patients who have responded to prior standard-of-care chemotherapy (phase 2a). This research is significant because it will evaluate a completely novel targeted therapy approach for patients with PDAC in specific disease contexts that include (i) aggressive, mesenchymal-like tumors (?intrinsic? sensitivity) and metabolically adapted tumors post-treatment with chemo- toxic agents (?adaptive? sensitivity), the current standard of care for this patient population. The research is innovative because it will evaluate a completely novel targeted therapy approach for patients with PDAC in these specific disease contexts, and it employs innovative biophysical and metabolic imaging characterizations. It is anticipated that this research may yield data relevant for other disease indications where metabolic dependencies may be similar, and our findings from this research may be a step toward developing IACS-010759 for clinical studies in other tumors as well.